Polymorphism in material science is the ability of a solid material to exist in more than one crystal form with each form having different orientations and/or conformations of the molecules in the crystal lattice. Polymorphism is important in the development of pharmaceutical ingredients, because each polymorph exhibits a unique set of physicochemical properties, due to the differences in structural arrangements in the crystals. Thus, solubility and dissolution rate may vary between polymorphs, leading to potential differences in bioavailability. Furthermore, mechanical properties such as flowability and compactability, which affect the processing properties of a compound, may be different. Stability and shelf life of a compound may also depend on the chosen polymorph. For these reasons it is valuable to screen for the existence of different polymorphic forms and to characterize discovered forms. Having different polymorphic forms to choose from provides new opportunities to improve the performance of a pharmaceutical product.
The polymorphic outcome of a chemical synthesis is determined by the crystallization conditions such as choice of solvent(s), rate of solvent addition, temperature, stirring rate, level of super-saturation, and level of impurities. Hence, different crystallization processes may give rise to different polymorphs. Polymorphs also have different stabilities and may spontaneously convert from one form to another.
Polymorphs can be distinguished from each other by a variety of techniques. Polymorphs exhibit distinct spectroscopic properties and can be identified using infrared spectroscopy, raman spectroscopy, and 13C-NMR spectroscopy. Due to the fact that each crystal form diffracts X-rays in different ways, X-ray powder diffractometry (XRPD) can also be used for identification. Furthermore, thermal methods such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) can provide information unique to a particular polymorph.
Pridopidine, i.e. 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine, is a drug substance currently in clinical development for the treatment of Huntington's disease. The hydrochloride salt of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine and a method for its synthesis is described in WO 01/46145. In WO 2006/040155 an alternative method for the synthesis of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine is described. When following these routes of synthesis a crystalline phase results with a melting point of 199° C. This crystalline phase is designated Form I.
Pridopidine hydrochloride Form I crystallises in the orthorhombic space group Pna21, with the lattice parameters a=10.5 Å, b=23.1 Å, c=6.9 Å, α=90° C., β=90° C., γ=90° C., and cell volume 1682 Å3. Form I is characterised by an X-ray powder diffractogram having the characteristic d-spacing's shown in Table 1, below, or a diffractogram substantially as depicted in FIG. 1; a DSC thermogram substantially as shown in FIG. 2, having an endotherm with an onset of about 199° C.; an IR spectrum substantially as depicted in FIG. 3; and a TGA thermogram substantially as depicted in FIG. 4.
TABLE 1d-spacing's, Pridopidine hydrochloride, crystalline Form I8.67.26.25.85.24.34.03.93.63.2
The dynamic vapour sorption (DVS) profile shows that Form I is non-hygroscopic below 80% RH, but deliquescent in excess of 80% RH (FIG. 5). TGA shows Form I to be a non-solvated form (FIG. 4). Form I is highly soluble in aqueous liquids with solubility in water of above 200 mg/ml.
The particle size—and shape distributions for Form I was investigated using image analysis and presented in Table 2 below. The D50 is 21 μm, and the D10 and D90 are 9 and 42 μm, respectively. The aspect ratio (AR) is obtained by dividing the longest dimension of the particles with the shortest one. Since the AR50 is 3.1 the particles are needle shaped.
TABLE 2Particle size (μm)D109D5021D9042Aspect ratioAR101.6AR503.1AR905.8
The bulk density and tapped density of Form I are 0.212 g/ml ±2.2%, and 0.264 g/ml ±1.1%, respectively.
A polymorph screening was performed on Pridopidine hydrochloride, including various methods of crystallization such as slurrying in organic solvents, solvent evaporation, cooling crystallization, crash cooling, and anti solvent addition. A wide selection of solvents was employed in order to increase the chance of finding new polymorphic forms. However, no forms besides the known Form I were discovered in the screening.